The Alzheimer’s disease Ab (AARP) ion channel.
AARP channel blockers inhibit the Ab peptide cytotoxicity.
Dr. Nelson Arispe
Professor of Anatomy, Physiology, and Genetics
Uniformed Armed Services University
Numerous reports have provided evidence that Ab peptides, the major components of plaques in the Alzheimer’s brain, are cytotoxic and may play a role in the pathogenesis of AD. It has been hypothesized that the primary cause of cellular damage and degeneration in the AD brain may be a toxic interaction between Ab peptides and nerve cells. One of the consequences of the interaction of Ab with the cell membrane is the generation of a calcium influx process that could, if extensive enough, create disturbances in intracellular calcium homeostasis. These disturbances play a pathological role in the neurodegeneration associated with Alzheimer’s disease. We have shown that the Ab peptides display affinity for acidic phospholipid membranes and spontaneously insert into lipid bilayers and neuronal membranes to form high conductance calcium channels. We proposed that the intracellular calcium increase observed after cell exposure to Ab is a consequence of the formation Ab calcium channels. In this presentation I will summarize experimental procedures designed to test the hypothesis that the interaction of Ab with membranes, both artificial and natural, results in the subsequent formation of Ab ion channels (AARP channel). I will describe the rationale to design specific channel blockers which we used for elaborating the architecture of the AARP channel. I will also show results from a diversity of experiments, on a variety of cells, which confirm that a specific AARP channel blocker removed the Ab cytotoxicity, supporting the view that Ab is cytotoxic largely due to the action of AARP channels in the cell membrane. Finally, I will show data to reinforce the premise that His residues within the AARP channel sequence participate in the pathway of ion flow.